With more than 200 million people infected, the Hepatitis C virus (HCV) poses a major health problem worldwide. The current therapy to treat HCV infections, which uses recombinant alpha interferon and ribavirin, is efficient only in less than 50% of the patients and chronically HCV infected patients can develop serious health problems which include liver cirrhosis and hepatocellular carcinoma. Thus, there is an urgent need for the development of new therapeutic strategies. HCV has its genome encoded by a positive-strand RNA, which contains an open reading frame flanked by 5'- and 3'-untranslated regions (UTRs). Despite the high mutational rate of the virus, the HCV RNA coding region, as well as its 5'- and 3'-UTRs contain evolutionary conserved sequences proposed to be involved in an intricate array of long-range interactions with each other. Although the molecular mechanisms of these interactions are not all clear, genetic data indicates that they play vital roles in the virus replication and translation. Thus, the inhibition of these interactions which involve regions of 100% conservancy among all HCV genotypes, is an attractive antiviral strategy, given their essential roles in the HCV life cycle, and this is the long term goal of this project, which has the following specific aims: Specific aim 1. Design and synthesis of peptide-nucleic acids which target conserved regions of the HCV genomic RNA essential for the viral replication and translation. Specific aim 2. Analyze the ability of the designed PNAs to disrupt the long-range interactions between regions of highly conservancy within the HCV RNA genome, inhibiting HCV replication and translation. PUBLIC HEALTH RELEVANCE: The significance of the proposed research is evident, as the peptide nucleic acid (PNA) inhibitors proposed to be synthesized and analyzed in these studies, target regions of 100% conservancy within the HCV genome. These ?-modified PNAs aim to disrupt essential long- range interactions between these regions, interactions whose biological significance for the viral life cycle has been established by genetic data. Thus, these studies have the potential to identify efficient inhibitors for HCV replication and translation, an imperatve task, considering the major health problem posed worldwide by the HCV infection, whose incidence is over 200 million people.